This invention relates to novel methods and compositions of matter for the amelioration of acetaminophen toxicity in humans.
It has recently been shown that ingestion of therapeutically recommended doses of acetaminophen (paracetamol) in humans for extended periods of time can cause massive hepatic necrosis. A. J. Ware, et al. Ann. Int. Med. 88:267-268 (1978); D. M. Rosenberg and F. A. Neelon, Ann. Int. Med. 88:129 (1978); J. D. Baker, Jr., Ann. Int. Med. 87:299-301 (1977); G. K. Johnson and K. G. Tolman, Ann. Int. Med. 87:302-303 (1977); D. M. Rosenberg et al. South Med. J., 70:600-601 (1977); and H. L. Bonkowsky et al. Lancet 2:1016-1018 (1978). Recent studies by Nebert with inbred mice have suggested that acetaminophen can cause cataracts in humans (Science 200:539-541, 1978). Finally, conditions which induce the liver enzymes responsible for the activation of acetaminophen such as alcohol or barbituates will markedly potentiate the hepatotoxicity of this compound.
The mechanism of acetaminophen toxicity is not fully understood. Editorial, Lancet (1975) 2, 1189; B. E. Walker et al., Clin. Sci. & Molecular Med. (1974) 47, 449-459.
Because such diverse compounds as cysteamine, methionine, cysteine, dimethylmercaptol, selenium and vitamin E have afforded varying degrees of protection in man and experimental animals against the hepatotoxicity of acetaminophen and because these compounds under certain circumstances can act as antioxidants, it has been suggested that other antioxidants would also provide protection. J. Kelleher et al., J. Int. Med. Res. (1976) 4, Supplement (4) 138-144.
Animal studies indicate that antioxidants can under some circumstances provide protection against the hepatotoxic effects of acetaminophen. For example, .alpha.-tocopherol provides such protection in vitamin E deficient rats. Walker et al., supra; J. Kelleher et al., supra. It has been reported that vitamin C also may provide such protection. Raghuram et al., Toxicology Letters, 2 (1978) 175-178. In an experimental study in man, although vitamin C caused a rapid and pronounced decrease in the excretion rate of acetaminophen sulfate, it did not affect the apparent half-life of drug, as evidenced by its rate of secretion in the urine, as such or as its glucuronide or its sulfate. J. B. Houston and G. Levy, J. Pharm. Sci., 65 (1976) 1218-1221. The authors stated that the specific interaction between acetaminophen and ascorbic acid probably was of little clinical significance under usual conditions, i.e., when acetaminophen is taken in single recommended doses as an analgesic or antipyretic. Other researchers concluded that the protective effects manifested by these vitamins cannot be attributed to their antioxidant activity because whereas vitamin E and propyl gallate reduce hepatotoxicity, diphenyl-p-phenylene-diamine (DDPD), an antioxidant in vitro and one which gives protection against CCl.sub.4 hepatotoxicity, enhances acetaminophen hepatotoxicity. J. Kelleher et al., J. Int. Med. Res, supra. These authors speculate that the modification of hepatotoxicity may result from an alteration of the activity of the specific components of the microsomol drug metabolizing enzyme system.
Surprisingly and notwithstanding the published literature reporting that some anti-oxidants may provide protection against the hepatotoxic effects of acetaminophen, I have found that the omnipotent antioxidants BHT (butylated hydroxytoluene) and BHA (butylated hydroxyanisole) profoundly enhance its hepatotoxicity. Because the general population consumes large amounts of these chemicals daily, because of their presence in a wide variety of food products, the likelihood of an increased incidence of hepatoxicity in persons taking repeated dosages of acetaminophen is self-evident.
Dimethyl sulfoxide has been shown to protect mice against the hepatotoxic effects of acetaminophen when administered up to one hour after administration of acute toxic amounts of acetaminophen. C. P. Seigers, J. Pharmac. 1978, 30, 375-377. Its activity was attributed to inhibition of microsomal oxidation of the drug by the hepatic mixed-function oxidase system to chemically reactive alkylating agents. On the other hand, this theory would fail to explain the inability of DMSO to protect mice against CCl.sub.4 hepatotoxicity, since this compound is also activated by the mixed function oxidase system. The authors therefore conclude that the antihepatotoxic actions of DMSO remain obscure.
A recent news release quotes a publication in "The Medical Letter" which reports a clinical study showing that acetylcysteine is effective in preventing hepatotoxicity if administered within 16 hours after an overdose of acetaminophen. Washington Post, Dec. 7, 1979, page A9. The authors chose acetylcysteine because of its chemical similarity to glutathionine, the substance which the body employs to detoxify the drug.
It is apparent from the foregoing that an effective method of protecting humans against acute acetaminophen hepatotoxicity has yet to be established. Moreover, there is no evidence to date that protection in humans against the chronic toxicity of acetaminophen at therapeutic multiple dosages is possible.
I have found that the anti-oxidant activity of vitamins C and E is not required to avoid the toxic effects of acetaminophen. Moreover, the drug-transport or the chemical similarity to glutathione also is not required. I have found that another class of compounds is effective not only to ameliorate the acute hepatotoxic effects of an overdose of acetaminophen but also to ameliorate the subacute chronic toxic effects of repeated dosages of therapeutic amounts of the drug.
It is an object of this invention to provide a novel method for ameliorating the toxic effects of acetaminophen in humans. It is another object to provide a method for the protection of humans against the acute hepatotoxic effects of an overdose of acetaminophen. It is a further object to provide a method for the protection of humans against the chronic toxic effects of multiple therapeutic doses of acetaminophen. It is still another object to provide novel compositions of matter suitable for use in the aforesaid methods. Other objects will be apparent to those skilled in the art to which this invention pertains.